Hemoglobin S polymerization is the primary determinant of the abnormal rheology associated with sickle cell anemia, which is characterized by chronic hemolysis and acute painful crises. Measurements of abnormal cell rheology in sickle cell anemia continue to provide correlations with clinical manifestations although the detailed mechanisms leading to such clinical endpoints are not well understood. The profound effect of hemoglobin S polymerization on cell rheology has given rise to a variety of therapeutic strategies designed to reduce the extent of intracellular polymerization. We have examined the solubility of hemoglobin S mixtures with hemoglobins A, A2 and F at varying oxygen saturations to determine the extent of hemoglobin S polymerization under physiologic conditions. A detailed analysis provides the means to predict the maximum extent of polymerization within the sickle hemoglobin containing erythrocyte. The theoretical model based on experimental data of polymerization of hemoglobin mixtures was used to analyze data obtained from the Parisian Prospective Study on Sickle Cell Disease in children with sickle cell anemia during the first two years of life. These data indicated that 3 of 21 children had a significantly greater predicted polymerization tendency due to early decreases in hemoglobin F. These individuals will be studied prospectively to ascertain the relationship among polymerization tendency and various clinical manifestations of sickle cell disease, as well as the effects of therapy. In our studies of the rheology of sickle cells we have noted that nucleated cells grown in the two-phase culture system will sickle upon deoxygenation. We are studying this phenomenon to learn about the relationship of intracellular polymerization and red cell membrane structure and because this process may occur in the marrow of sickle cell patients and have pathophysiological importance. Lastly, we are continuing our theoretical analyses of the resistance to flow of sickle cells as a function of polymerization, cell density and pulsatile forces to better understand processes in the peripheral blood vessels of patients.